Chronic pain is a significant medical problem. Its treatment, in particular chronic neuropathic pain, remains an area of unmet therapeutic need. An important potential group of drugs for the treatment of neuropathic pain are compounds which act as antagonists at the N-methyl-D-aspartate (NMDA) receptor. Drugs from this class have also been shown to enhance the analgesic effect of morphine and to inhibit tolerance development to this opioid. Despite their great promise as analgesics, the clinical usefulness of the only available NMDA receptor antagonist, ketamine, has been limited due to its psychotomimetic, sedative and motor side effects. This has prompted an effort towards identifying other NMDA receptor antagonists which retain analgesic properties but with a more acceptable side effect profile. Phase I STTR funding for this project has demonstrated that the novel NMDA receptor antagonist, norketamine (NK) and its enantomers [R(+) and S(-)-NK] have analgesic properties in a rodent model of neuropathic pain. The majority of side effects are with the R(+)-enantiomer. Thus, we have established the feasibility that norketamine, specifically S(-)-NK, has the potential for development as a novel agent for the treatment of neuropathic pain. The ultimate objective in the proposed Phase II STTR funding is to develop an NMDA receptor antagonist with fewer and more tolerable side effects for the treatment of chronic pain. The specific aims of the Phase II STTR proposal are to: 1) further characterize the pharmacologic profile of S(-j-NK, in comparison to R(+)- NK, in established rat models of pain and behavior; 2) perform non-cGMP bulk synthesis of S(-)-NK for preclinical studies; 3) evaluate the oral bioavailability, assess the metabolic profile, and determine the optimal oral dose of S(-)-NK in the rat; 4) provide a bulk manufacturing process for the API, formulate an oral capsule dosage form of S(-)-NK and obtain cGMP S(-)-NK and cGMP placebo for use in the Phase I clinical trial; 5) evaluate toxicological properties of S(-)-NK including neurotoxicity; 6) conduct a Phase I clinical trial to assess the safety of S(-) NK. In summary, Phase I STTR findings have established the feasibility that S(- )-NK is a viable candidate for further development as a drug for neuropathic pain. The Phase II STTR proposal will build upon Phase I STTR findings to further characterize the pharmacology and toxicology of S(-)-NK, to obtain an Investigational New Drug application, with the overall goal of proceeding to a Phase I clinical trial in humans. The development of a clinically useful drug for chronic neuropathic pain will have potential broad application for the treatment of pain including cancer, AID'S, neuropathy, diabetic neuropathy, complex regional pain syndrome and radiculopathy. [unreadable] [unreadable] [unreadable]